1. Field of the Invention
The present invention relates to a method for drying a substrate having probes immobilized on the surface thereof.
2. Description of the Related Art
Measurements and detection of biological specimens have been urgently required with the advance of the biotechnology. However, different from chemical substances obtained by chemical synthesis methods, strict measurements of the biological specimen are often difficult for the following reasons:    1) the properties of the biological specimens are quite diverse;    2) the quantity of the sample available is very small; and    3) samples having similar physical properties should be discriminated.
While various methods have been devised for measuring these specimens, the most noteworthy measuring technique among them utilizes a solid phase substrate. In the measuring technique using the solid phase substrate, a probe that specifically binds a specimen as a detection object is immobilized on the surface of a solid such as a glass substrate, a test sample labeled with a fluorescent substance is allowed to react with the substrate, and the components of the test sample are assayed by bonding of the test sample, if any, to the probe.
This measuring technique is mainly of note for the following reasons (advantages):    1) a quite minute quantity of the test sample can be measured by reducing the amount (area) of the detection probe immobilized on the substrate, and the quantity of the sample becomes very small;    2) many test items can be simultaneously measured by aligning various kinds of detection substances on the substrate; and    3) handling of the system is easy, since the measurement is possible using a solid phase in place of a liquid phase.
The measurement of the sample using the solid phase substrate has been applied, for example, to detection of sequences of a nucleic acid. Many kinds of single strand DNAs (DNA probes) having various sequences are immobilized on the substrate as an array, and DNAs labeled with a fluorescent pigment are allowed to hybridize with the probes. The fluorescent substance is immobilized (hybridized) on the substrate where the test sample contains a sequence complementary to the DNA on the substrate, and the sequence contained in the test sample can be determined with reference to the sequence of the DNA probe immobilized on the substrate. For example, Takara Bio Inc. sells DNA micro-arrays prepared by immobilizing several hundreds kinds of probe DNAs immobilized on slide glasses, and these products are used for analysis of various genes.
While a number of methods have been devised for manufacturing the DNA micro-array, the frequently used method comprises dissolving a DNA that serves as the probe in a given solution, adhering the DNA solution at a sharp tip of a needle, and supplying a quite minute quantity of the DNA solution onto a glass substrate after an appropriate surface treatment. The DNA micro-array manufactured by this method is subjected to drying after a prescribed immobilizing treatment. When the probe component remaining on the surface of the substrate is to be washed away, the substrate is washed with purified water or a buffer solution followed by drying the substrate.
Japanese Unexamined Patent Laid-Open No. 2001-021558 discloses a method for drying droplets after spotting without washing. Japanese Unexamined Patent Laid-Open No. 2000-295990 discloses a method in which the probe is dried by washing with ethanol after washing with a buffer solution after spotting.
When the probe is not cleaned after preparing the DNA micro-array, the components in the probe solution precipitate in the spotting region, and the function of the probe may be deteriorated by the precipitate. While the surface of the substrate is often cleaned to avoid the function of the probe from deteriorating, fine droplets of the cleaning solution may be left behind immediately after washing with the buffer solution. Many water molecules and buffer components may be left behind on the surface of the substrate from a microscopic point of view. Conventionally, the droplets may be blown away by placing the substrate in a high speed air stream, or placing the substrate in a centrifuge. However, salts contained in the buffer solution may precipitate at the boundaries among the droplets in this droplet removing step. Precipitation of the salts as the solute may cause various errors and irregularity in the use of the DNA micro-array as a result of increased salt concentration in the DNA hybridization process and non-specific adsorption of the sample. Moreover, the fact that the probe on the surface of the substrate is unevenly exposed to an environment of high salt and solute concentration is not preferable, since the function of the probe may deteriorate, although this phenomenon occurs in microscopic regions.
As a countermeasure to the phenomena above, the substrate is washed with purified water in order to remove as much solute in the residual droplets as possible, or the substrate is dried using volatile alcohols, such as ethanol. However, much labor is required to completely remove the precipitate, and it is often difficult to avoid the precipitate from being irregularly left behind even when the amount of the residual precipitate is permissible. These problems occur to the same extent as when the buffer solution is used. Exposing the probe to a hot organic solvent is also not preferable, since the probe faces a high risk of having its function deteriorate. It may be conjectured that the probe interacts with the surface of the solid phase during storage in a dry state after the drying step, and the function of the probe is deteriorated.